Education:

B.S., University of Wyoming, 1976
B.S. Pharm, University of Wyoming, 1977
Ph.D., University of Washington, 1982

Research Interests:

The primary focus in my laboratory is on drug metabolism and disposition. A major area of research involves studies on the mechanisms of metabolic interactions of antiepileptic drugs with a focus on drug interactions involving the P450 system and glucuronidation in the elderly. Interactions between antiepileptic drugs such as phenytoin and cabamazepine and antidepressants are being examined with a bank of human liver microsomes from elderly donors. Stable isotope pharmacokinetic studies with phenytoin, carbamazepine, valproic acid, and lamotrigine are being conducted in elderly patients to understand the impact of aging on drug metabolism. Interactions involving the glucuronidation of valproic acid and lamotrigine are also being studied. In order to identify and quantitate drugs and their metabolites in biological fluids, sophisticated analytical techniques such as HPLC, GC, CE, and mass spectrometry are developed in the laboratory.

Another area of research involves mechanistic studies on the metabolism and hepatotoxicity of naltrexone. Naltrexone is being used by our collaborator, Dr. Suk-Won Kim for treatment of compulsive addictive disorders such as pathologic gambling and kleptomania. In the course of clinical trials, we found several patients developed elevations in liver transaminases indicative of hepatotoxicity. All of these patients also were taking non-steroidal anti-inflammatory drugs. We have found that some NSAIDs are inhibitors of naltrexone glucuronidation. When the glucuronidation of naltrexone and beta-naltrexol is inhibited, more of the drug is metabolized by a P450 pathway to reactive quinone or quinone methide. We have recently identified glutathione conjugates of naltrexone in hepatocyte incubations and in human liver microsomes supplement with glutathione on a linear quadrupole-ion trap mass spectrometer. Studies are underway to determine if these conjugates are formed in humans.

Finally, a major collaborative initiative involves the development of a bioartificial liver that contains collagen-entrapped hepatocytes in a hollow-fiber reactor. Several approaches are being examined in an effort to maximize the biotransformation activity of the cultured pig cells. Optimization strategies include induction of P450 and UDP-glucuronosyltransferases, alteration of extracellular matrix, improving cell-cell contact by culturing hepatocytes into spheroidal aggregates, and targeted gene delivery to overexpress key enzymes involved in detoxification of waste products and xenobiotics. The device has been successfully tested in animal models of liver failure. Systematic scale-up is underway to test the device in patients with acute liver failure who are awaiting a liver transplant. We are also using hepatocyte models to study the mechanism of action and metabolism of several botanical hepatoprotectants e.g. milk thistle and Schisandra flavolignans.

More detailed information about the bioartificial liver is available.

Publications:

Otteneder MB, Knutson CG, Daniels JS, Hashim M, Crews BC, Remmel RP, Wang H, Rizzo C, Marnett LJ.  In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M1dG. Proc Natl Acad Sci U S A. 103(17):6665-6669 (2006).

Kirstein MN, Hassan I, Guire DE, Weller DR, Dagit JW, Fisher JE, Remmel RP. High-performance liquid chromatographic method for the determination of gemcitabine and 2',2'-difluorodeoxyuridine in plasma and tissue culture media. J. Chromatogr B Analyt Technol Biomed Life Sci. 835(1-2):136-42 (2006).

Kirstein MN, Brundage RC, Elmquist WF,  Remmel RP, Marker PH, Guire DE, Yee D, Characterization of an In vitro Cell Culture Bioreactor System to Evaluate Anti-Neoplastic Drug Regimens. Breast Cancer Res. Treat. 96(3):217-25 (2006).

Kim SW, Grant JE, Yoon G, Williams KA, Remmel RP. Safety of high-dose naltrexone treatment: hepatic transaminase profiles among outpatients. Clin Neuropharmacol. 29(2):77-9 (2006).

Nagar S, Remmel RP,  Uridine-glucurosonyltransferase (UGT) Pharmacogenetics and Cancer.  Oncogene 25(11):1659-72 (2006).

Kumar A, Mann HJ, Remmel RP, Determination of the consitituents of Telazol® - tiletamine and zolazepam in plasma by gas chromatograpy-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Jun 10; [Epub ahead of print] PMID: 16769259 RJ

Nyberg SL, Hardin J, Amiot B, Argikar UA, Remmel RP, Rinaldo P. Rapid, large-scale formation of porcine hepatocyte spheroids in a novel spheroid reservoir bioartificial liver. Liver Transpl. 11(8):901-910 (2005).

Burleigh ME, Babaev VR, Patel MB, Crews BC, Remmel RP, Morrow JD, Oates JA, Marnett LJ, Fazio S, Linton MF.  Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice. Biochem Pharmacol. 70(3):334-42 (2005).

Jacobson P, Rogosheske J, Barker J,  Green K, Ng J, Weisdorf D, Tan Y, Long J, Remmel R, Sawchuk R, McGlave P, Relationship of Mycophenolic Acid Exposure to Clinical Outcome after Hematopoietic Cell Transplantation Clin. Pharmacol. Exp. Ther. 78(5):486-500 (2005).

Chen S, Beaton D, Nguyen N, Senekeo-Effenberger K, Brace-Sinnokrak, E, Argikar U, Remmel RP,  Trottier J, Barbier O,Ritter JKTukey RH Tissue Specific, Inducible, and Hormonal Control of the Human UDP-Glucuronosyltransferase-1 (UGT1) Locus. J. Biol Chem. 280(45):37547-57 (2005).

Peng JZ, Remmel RP, Sawchuk RJ.  Inhibition of cytochrome P4501A by tacrine: in vitro studies. Drug Metab Dispos. 32(8) :805-12 (2004).

Perlman DC, Segal Y, Rosenkranz S, Rainey PM, Peloquin CA, Remmel RP, Chirgwin K, Salomon N, Hafner R; ACTG 309 Team.  The clinical pharmacokinetics of pyrazinamide in HIV-infected persons with tuberculosis. Clin Infect Dis. 38(4):556-64 (2004).

Nagar S, Remmel RP, Hebbel RP, Zimmerman CL. Metabolism of opioids is altered in liver microsomes of sickle cell transgenic mice.  Drug Metab Dispos. 32(1):98-104 (2004).

Remmel RP, Crews BC, Kalgutkar AS, Marnett LJ,  Studies on the metabolism of the Selective Cyclooxygenase-2 Inhibitor, Indomethacin Phenethylamide, in Rat, Mouse, and Human Liver Microsomes. Identification of Active Metabolites.  Drug Metab. Disp.  32:113-122 (2004).

Tzanakakis ES, Waxman D, Hansen LK, Remmel RP, and Hu W-S, Long-term enhancement cytochrome P450 2B1/2 activity in rat hepatocyte spheroids through adenovirus-mediated gene transfer.  Cell Biol. Toxicol. 18:13-27 (2002).

Jacobson PA, Green K, Birnbaum A, and Remmel RP, Cytochrome P450 enzymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa.  Cancer Chemother. Pharmacol. 49:461-467 (2002).

Tran TA, Leppik IE, Blesi K, Sathanandan ST, Remmel RP, Lamotrigine clearance during pregnancy.  Neurology 59(2):251-255 (2002).

Remmel RP. (2002) Review of Human UDP-glucuronosyltransferases and Their Role in Drug-Drug Interactions.  In:  Drug-Drug Interactions. Ed. A.D. Rodrigues, Marcel-Dekker, New York, p. 89-121.

Nelson MH, Birnbaum AK, Remmel RP, Inhibition of phenytoin hydroxylation in human liver microsomes by several selective serotonin reuptake inhibitors.  Epilepsy Research  44:71-82 (2001).

Tzanakakis ES, Hsiao C-C, Matsushita T, Remmel RP, and Hu W-S, Probing enhanced cytochrome P450 2B1/2 activity in rat hepatocyte spheroids through confocal laser microscopy.  Cell Transplantation 10:329-342 (2001).

Kim SW. Grant JE. Adson DE. Remmel RP. A preliminary report on possible naltrexone and nonsteroidal analgesic interactions. [Letter] J. Clin. Psychopharmacol. 21(6):632-634 (2001).